PD-1 derived CA-170 is an oral immune checkpoint inhibitor that exhibits preclinical anti-tumor efficacy

Commun Biol. 2021 Jun 8;4(1):699. doi: 10.1038/s42003-021-02191-1.


Small molecule immune checkpoint inhibitors targeting PD-1 and other pathways may offer advantages including ease of dosing, ability to manage immune-related adverse events (irAEs) due to their shorter pharmacokinetic exposure and opportunity to target more than one pathway for improving efficacy. Here we describe the identification and characterization of CA-170, an amino acid inspired small molecule inhibitor of PD-L1 and VISTA derived from the interface of PD-1 and PD-L1. CA-170 exhibited potent rescue of proliferation and effector functions of T cells inhibited by PD-L1/L2 and VISTA with selectivity over other immune checkpoint proteins as well as a broad panel of receptors and enzymes. Observed blocking of PD-L1 signaling and binding to PD-L1 in the cellular context without preventing the assembly of PD-1:PD-L1 complex support the formation of a defective ternary complex as the mechanism of action of CA-170. Oral administration of CA-170 resulted in increased proliferation and activation of T cells in the tumor, and significant anti-tumor efficacy in a number of immunocompetent mouse tumor models either as a single agent or in combination with approved therapeutics. These results prompted the advancement of CA-170 to human clinical trials.

MeSH terms

  • Administration, Oral
  • Animals
  • Antineoplastic Agents / administration & dosage
  • Antineoplastic Agents / chemistry
  • Antineoplastic Agents / therapeutic use*
  • Cell Line, Tumor
  • Colonic Neoplasms / drug therapy*
  • Drug Discovery
  • Female
  • Humans
  • Immune Checkpoint Inhibitors / administration & dosage
  • Immune Checkpoint Inhibitors / chemistry
  • Immune Checkpoint Inhibitors / therapeutic use*
  • Male
  • Mice, Inbred BALB C
  • Mice, Inbred C57BL
  • Programmed Cell Death 1 Receptor / antagonists & inhibitors
  • Small Molecule Libraries / administration & dosage
  • Small Molecule Libraries / chemistry
  • Small Molecule Libraries / therapeutic use*


  • Antineoplastic Agents
  • Immune Checkpoint Inhibitors
  • Programmed Cell Death 1 Receptor
  • Small Molecule Libraries